2003 Albert Lasker Clinical Medical Research Award

Anti-TNF for treating rheumatoid arthritis

The 2003 Albert Lasker Award for Clinical Medical Research honors two scientists who discovered anti-TNF therapy as an effective treatment for rheumatoid arthritis and other autoimmune diseases. Despite initial skepticism from the research community about their idea, Marc Feldmann and Sir Ravinder Maini transformed their findings in the laboratory into a powerful treatment. The therapy they developed has brought relief and vitality to hundreds of thousands of people worldwide, and promises to better the lives of even more individuals as it proves effective against additional debilitating illnesses.

All autoimmune diseases — conditions in which the body turns against itself — arise from multiple causes and involve a large number of misbehaving molecules. In particular, proteins called cytokines, which carry signals between cells to orchestrate the fight against invading microorganisms, act up and provoke ferocious inflammation. When Feldmann and Maini began their work in 1984, most scientists doubted that neutralizing a single molecule would quiet such complicated multifactorial systems. Yet the researchers discovered that crippling one of the cytokines — TNF — pacified the entire inflammatory entourage.

They made their breakthroughs by studying rheumatoid arthritis, a chronic autoimmune disease that afflicts approximately 0.5 to 1.0 percent of the population. The illness attacks the joints; inflammation and progressive damage to cartilage and bone causes pain and stiffness, makes movement difficult, and leads to serious disability. Conventionally, patients took aspirin or other nonsteroidal anti-inflammatory drugs to soothe their discomfort, but these drugs didn't halt disease progression. Agents such as corticosteroids and so-called disease-modifying anti-rheumatoid drugs posed problems because they helped only half of the patients and caused side effects. No treatment healed the joints or completely impeded damage to cartilage and bone.

In the early 1980s, Feldmann, a medically trained immunologist from Australia, was working at University College, London, and had begun studying a different autoimmune condition called Graves' disease, which causes the thyroid to become overactive. In this illness, particular non-immune thyroid cells take on unusual properties, acquiring molecules (such as HLA class II proteins) that allow them to stimulate an immune reaction that leads to inflammation. Scientists knew that these same molecules cropped up inappropriately in other autoimmune diseases as well, and that cytokines stimulate production of them.

Feldmann proposed that cytokines stir up autoimmune disease. He decided to test this idea; as a first step, he would check whether tissue afflicted with an autoimmune illness contained excess cytokines. He chose rheumatoid arthritis, because it would provide the opportunity to study tissue at the height of inflammation, which was not possible in Graves' disease: Doctors routinely remove diseased tissue from rheumatoid arthritis patients to relieve symptoms.

A mutual acquaintance recommended that Feldmann meet Maini, a leading rheumatologist and researcher at the Arthritis Research Campaign's Kennedy Institute of Rheumatology at Imperial College in London. With one foot in the lab and one foot in the clinic, Maini had good access to the human tissue that would be needed for the investigations. The notion that deranged cytokine behavior fostered rheumatoid arthritis had snagged his attention as well, and the two scientists teamed up, hoping eventually to harness the chaos.

By the early 1980s, scientists were developing new research tools that could identify individual cytokines — an important advance because these chemical messengers often show up in groups. The ability to catalog which cytokines were present — and to foil them separately — would prove crucial to Feldmann's and Maini's analysis.

The two researchers, as well as others, showed that the joints of people with rheumatoid arthritis teem with proinflammatory cytokines. Furthermore, Feldmann and Maini found that the diseased joint cells themselves produced these cytokines in an uncontrolled fashion. When the researchers grew the cells from afflicted knee joint tissue in culture dishes, the mixture churned out cytokines continuously for six days; during a healthy inflammatory response, the signaling molecules appear only briefly. The observation that arthritic cells gush cytokines implied that the normal means of tempering the immune response had gone awry.

The identity of the cytokines hinted at the underpinnings of specific disease features. For example, one of the cytokines in the joints recruits immune cells to sites of tissue injury, an observation that could explain the local inflammation; another activates antibody-producing cells, and might thus spur the output of antibodies that ravage the body's own tissues. Despite these potential windows into the molecular mechanisms of the disease, the results vexed scientists. Many of the cytokines present in the joints perform overlapping duties. A treatment that disarmed one cytokine could prod another to work overtime, experts reasoned, and wouldn't quell the disease.

Maini and Feldmann, however, suspected that a single cytokine might act as a fire alarm to jolt the entire system into action. Studies had shown that a cytokine called IL-1 causes joint damage in animal tissue. Furthermore, mice suffering from a condition that mimics some aspects of rheumatoid arthritis produced IL-1 in their inflamed joints. These observations pointed to IL-1 as a rheumatoid arthritis suspect. The researchers wanted to know whether they could find a cytokine that would kick-start the disease — and in particular, IL-1 production.

As a first step, Feldmann and Maini tested whether several cytokines emitted by joint cells in culture dishes influenced the manufacture of IL-1. To accomplish this task, they added antibodies that knocked the cytokines out of commission. Most antibodies had no effect, but one that foiled TNF quashed IL-1 output. Feldmann and Maini then conducted the converse experiment, adding instead an antibody that disabled IL-1; TNF quantities remained unchanged. Additional work showed that the anti-TNF antibodies also squelched the manufacture of other proinflammatory cytokines. These results and those from other groups indicated that TNF played a key role in governing the creation of cytokines and other inflammatory molecules: Blocking this single molecule could apparently turn down the entire inflammatory response. To move toward their goal of treating humans, the researchers wanted to test whether similar events occurred in mice with arthritis.

Injecting collagen — a component of connective tissue, which includes cartilage and bone — into a particular strain of susceptible mice sparks a condition that shares some key features with rheumatoid arthritis. In particular, a comparable immune response erupts in the joint and a related type of tissue damage develops. Using collagen, the researchers induced rheumatoid arthritis-like symptoms in mice and then injected anti-TNF antibody. This treatment reduced swelling and joint destruction. Several other groups — in New York City, Geneva, and Athens — independently generated similar results, supporting the idea that an excess of TNF can incite the whole disease.

This success in animals gave the researchers confidence to attempt therapy in patients. But the antibody they had used in the rodent studies wouldn't suffice because it inactivated mouse, but not human, TNF. The researchers had antibody that bound human TNF, but it had been made in mice and would likely cause dangerous side effects as the human immune system mounted a response against it; furthermore, this immune response would expel the antibody. Feldmann and Maini wanted instead a molecule that bound human TNF and contained a large portion of a human antibody. A person's body would treat the resulting antibody more normally and wouldn't reject it.

In attempts to fight sepsis, a number of companies had developed such chimeric human-mouse antibodies as well as other compounds that knocked TNF out of commission. However, at the time (early 1990s), the conventional wisdom in the pharmaceutical industry was that therapeutic antibodies wouldn't thwart chronic diseases. Humans wouldn't tolerate antibodies that were part human and part mouse over the long term, the thinking went; the immune system would notice the portion from mouse and attack it, limiting the benefit and inducing dangerous side effects. Furthermore, many experts thought that disrupting the cytokine system would spur it to reorganize; inflammation would flare up again and patients would wind up back where they started. Finally, given the number of cytokines in diseased joints, scientists were still skeptical that hobbling a single cytokine would relieve symptoms. Although the strategy had triumphed in mice, rodent and human physiology differs and many apparently promising therapies had failed to transfer from animals to people. Even Feldmann and Maini didn't think that an antibody-based therapy would prove ideal in the long run. Producing these molecules is very costly and thus, therapeutic antibodies — even if they worked — wouldn't flourish in the marketplace.

However, if Feldmann and Maini could remedy disease in humans by blocking their target molecule, they figured they could eventually develop a less expensive drug that would mimic the antibody. Therefore, they were eager to know whether their novel scheme would work.

Fortunately, one of Feldmann's former visiting scientists named James Woody had taken a position as research director at a company called Centocor Inc. in Malvern, Pennsylvania, which had created a chimeric anti-TNF antibody for use against sepsis. Woody was amenable to Feldmann's and Maini's idea, and Centocor agreed to provide material for a preliminary test in humans.

In 1992, Feldmann and Maini, working together at the Kennedy Institute by this time, performed the first clinical trial of anti-TNF therapy for rheumatoid arthritis. Because no one knew whether it would trigger harmful side effects in patients who were already ill, the researchers recruited only patients who had not responded to other therapies and had no other treatment options. They injected the antibody, called cA2 at the time — subsequently known as infliximab, and now Remicade — into the bloodstream.

Within a few hours, the patients reported dramatic symptomatic relief; they felt more energetic and their joints had loosened up. Within several weeks, previously incapacitated people were playing golf and climbing stairs. Maini and Feldmann were thrilled — but they worried about the placebo effect — a phenomenon in which people feel better even when they're receiving a fake drug. Objective measures, however, indicated that the disease was retreating. Quantities of a blood-borne protein that accompanies inflammation dove and joint swelling subsided.

Between 6 and 12 weeks after finishing the two-week treatment, symptoms recurred. The researchers re-administered the antibody to eight of the 20 patients, which again considerably benefited them. Eventually disease returned, indicating that blocking TNF temporarily did not permanently cure individuals with resistant disease. However, the antibody seemed safe and the results justified further trials. Feldmann and Maini presented their findings at a meeting in 1992, drawing the attention of other companies, which started brushing up their own anti-TNF agents for possible use in combating rheumatoid arthritis.

The striking initial success persuaded Centocor to support the first multi-center clinical trial of TNF blockade in four European cities. To generate formal proof that the treatment helps patients, the researchers set up a rigorous experiment in which two groups of patients would receive the active drug in different doses and another would receive a placebo; neither doctors nor patients would know who was in which group. The researchers injected the agent of choice once into 72 people and then tracked disease over a period of four weeks. Again, joints became less tender and swollen, and amounts of the blood-borne inflammatory marker plummeted.

These results heartened Feldmann and Maini, but rheumatoid arthritis is a long-term disease, and their patients eventually relapsed. To test whether re-treatment might further fend off the disease, they conducted another study in which they administered five infusions over a period of 14 weeks and observed patients for six months. This tactic kept the disease on hold, indicating not only that people could tolerate the antibody over the long term, but also that it continued to exert a therapeutic effect. In this study, the researchers also assessed whether another drug enhanced the anti-TNF regimen. Feldmann and Maini knew from their work in animals that depleting a particular class of immune cells amplified the effects of the anti-TNF antibody. A compound called methotrexate, the most commonly used anti-rheumatic drug, hinders the activity of these same immune cells, so the researchers administered methotrexate along with the antibody to half of the patients. Their predictions panned out: Methotrexate magnified the positive effects of anti-TNF, and combination therapy is currently used for the majority of rheumatoid arthritis patients who undergo long-term anti-TNF therapy.

The treatment was clearly performing well by every yardstick they had used so far, but Maini and Feldmann, joined by Peter Lipsky in Dallas and several other North American and European groups, wanted to measure structural joint damage per se, which they could track over a long period of time with X-rays. A year of treatment with anti-TNF antibodies and methotrexate every eight weeks arrested cartilage and bone devastation in about half of 428 patients. Not only did joint destruction stall in these individuals, but the results hinted that the body managed to repair previous injury. These results gave Centocor sufficient results to apply for FDA approval of their antibody. Even after two years on the combination regimen, the patients continued to do well.

Although Centocor was the first company to sign on to anti-TNF antibody trials for rheumatoid arthritis, Feldmann and Maini's 1992 disclosure of their results prompted other companies to compete vigorously and test their own anti-TNF agents. Wyeth/Immunex's etanercept (Enbrel) was approved in November 1998, a year before Centocor's drug was approved for use in combination with methotrexate for rheumatoid arthritis. Three drugs that restrain TNF — Remicade, Enbrel, and Abbott's adalimumab (Humira) — are now licensed in the United States and in Europe. Patients inject themselves under the skin from twice a week (Enbrel) to once every two weeks (Humira), or come to the clinic every eight weeks for an infusion into a vein (Remicade). All of these agents pack an effective punch; for many patients, they are continuing to keep the disease in check even after five years of treatment. Several more TNF blockers have been tested and appear promising in clinical studies, but have not yet been approved.

The clinical trials established that the treatment helps many people — but they also revealed a gap. Approximately 60 percent of the individuals studied responded to anti-TNF therapy. Because these patients included only those with severe disease whose illness defied other therapies, that statistic is impressive — but it leaves room for improvement. In an attempt to help people who derive no benefit from treatment and to better understand the molecular mechanism of the disease, Feldmann and Maini have dug deeper into how anti-TNF therapy works. As predicted, amounts of particular cytokines in the blood and joints ramp down after treatment and, presumably as a consequence, inflammatory cells stop gravitating toward the ailing joints. Furthermore, new blood vessels — which normally nourish the congregating immune cells — no longer form. Together, these observations suggest that the treatment scrambles signals that would otherwise draw troublemaking cells to the joints and minimizes their ability to gather. Additional experiments hint at how the anti-TNF agents deter — and possibly even heal — joint damage. The treatment, for example, depletes a particular type of tissue-destroying enzyme. Such information might provide information that could goad researchers toward the development of alternative treatments for patients with recalcitrant disease.

The success of anti-TNF-based therapy for rheumatoid arthritis led to clinical trials to assess these agents' ability to curb other chronic illnesses in which cytokines become unruly. The first was Crohn's disease, an inflammatory condition of the bowel. Anti-TNF antibody ameliorated the illness, and Remicade is now approved for the treatment of severe Crohn's disease. More recently, scientists have conducted successful trials of agents that foil TNF in other chronic diseases of excess inflammation, and the drugs are now licensed to treat juvenile rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis.

All in all, therapies that muzzle TNF have benefited approximately 400,000 people, approximately 70 percent of whom suffer from rheumatoid arthritis. By pursuing their vision, Feldmann and Maini turned a speculative hypothesis into a potent discovery that will aid myriad patients for years to come.

Award presentation by Craig Thompson

To understand the achievements of this year's Lasker Clinical Medical Research awardees, it is important to consider the vital role the immune system plays in protecting us from infection. The immune system must constantly distinguish our own cells from those of the viruses and bacteria to which we are exposed. Its critical role has been demonstrated by the devastating infections experienced by children born without an intact immune system, by patients whose immune function has been destroyed by diseases such as AIDS, or when a cancer patient's immune cells are damaged as a result of the side effects of chemotherapy. Thus, the complex immune system we have evolved plays a vital role in maintaining our health and survival. Harnessing its power to prevent disease through vaccination is one of the most important medical advances of the last century.

One price which we pay for having an immune system that can protect us from infectious organisms is that it will occasionally suffer errors in the ability to distinguish between our own cells and those of invading microbes. The chances are small during any single infection that such an error will occur. However, when this risk is summed over a lifetime of exposures, there is an increasing chance that an individual will suffer the consequences of the immune system's mistaken attack on our own tissues. Such disorders are collectively known as autoimmune diseases. Although in most instances these diseases do not have the acute consequences of a heart attack, stroke, or cancer, they are a major cause of chronic illness and disability. One of the most prevalent autoimmune diseases is rheumatoid arthritis, a disease in which the body's immune system attacks the joints. Rheumatoid arthritis afflicts approximately one percent of the population. It affects women more frequently than men, and its incidence is relatively constant throughout the world, independent of geographic location, race, and socio-economic status. The disease is insidious in onset, the joints involved can vary, and symptoms often wax and wane, making the diagnosis difficult to establish in its early stages. However, once established, rheumatoid arthritis is a chronic and progressive illness, spreading like a wildfire through each of the joints. By the time most patients are diagnosed, the complications of chronic inflammation are so destructive that a vicious cycle of inflammatory joint damage followed by further activation of the immune system results in an endless spiral of disease.

Over the last 50 years, physicians have made little progress in improving the treatment of chronic autoimmune diseases such as rheumatoid arthritis. Although anti-inflammatory treatments such as aspirin can decrease the patient's symptoms, they do nothing to halt the progressive nature of the disorder. Steroids can suppress the chronic pain syndrome associated with these autoimmune diseases, but do little to alter the natural progression of the disease and are associated with significant long-term side effects. Until recently the greatest hope of intervening in the disease came with treatments using cancer chemotherapeutic agents that are used to destroy the immune cells causing the inflammation. Unfortunately, the use of these drugs involves all the complications associated with cancer treatments.

Beginning in the early 1980s, immune cells were discovered to release molecules, termed cytokines, which served to control the immune response. Investigation of the properties of these cytokines led to the clinical introduction of blood cell recovery factors such as erythropoietin for the treatment of anemia and the use of interferons in the treatment of cancer. To date, over 100 of these cytokines have been discovered, many with overlapping functions. Immunologists have rationalized the existence of so many cytokines because, as we have learned in this age of terrorism, the best defenses have multiple redundant back-ups built into the system.

At the time that Ravinder Maini and Mark Feldmann began the work for which they are being recognized today, it was clear that the joints of rheumatoid arthritis patients were a conflagration of these inflammatory molecules, the properties of any one of which is enough to induce an inflammatory response that would destroy the joints of the afflicted patients. This led to the 'conventional wisdom' that autoimmune diseases could not be treated by blocking the actions of any single cytokine.

At this juncture, it is important for me to point out that Mark Feldmann and Ravinder Maini are not conventional characters. Mark Feldmann is Australian by birth and his desire to work at the interface of medicine and science led him, after medical school and residency, to return to school where he earned a PhD in immunology at the University of Melbourne studying with Gus Nossal, one of Australia's preeminent scientists. Upon graduation, instilled with a burning desire to prove himself, Mark moved his family halfway across the world to London to take up a position in clinical immunology. It was in London that he met Ravinder Maini. In Maini, Feldmann found a kindred spirit. "Tiny," as Maini is known to his friends, had grown up to his current impressive stature in East Africa. During his childhood in Africa, Maini learned from his father the satisfaction of a life dedicated to the service of others. His father had served as mayor of Kampala during the troubled time preceding Ugandan independence and was recognized for his service in that part of the world by being knighted by Queen Elizabeth in 1957. It was with the desire to make a contribution to the world as his father had, that Tiny began his secondary education in England. However, during his undergraduate days in Cambridge, his interest turned to medicine. At the time he met Feldmann, Maini was working as a consultant rheumatologist at the Arthritis Research Campaign's Kennedy Institute of Rheumatology in London.

From the beginning, Feldmann and Maini shared the belief that the damage caused during an autoimmune disease resulted from the incendiary properties of cytokines that immune cells produce. They also believed that there existed a 'spark' that initiated the inflammation during the early phases of the disease. With this underlying hypothesis they began a systematic study of the role each cytokine played in the inflammation observed in biopsy samples from the damaged joints of patients with rheumatoid arthritis. In less than two years, they found their spark, TNF or tumor necrosis factor, a cytokine so named because it was capable of damaging even the most malignant cell.

The idea that a single cytokine was responsible for the initiation and maintenance of joint destruction in rheumatoid arthritis was viewed by most immunologists with skepticism. Furthermore, most argued that even if Feldmann and Maini were right, there didn't seem to be a way to use this information to develop a treatment. However, an experiment of nature showed the way. Another autoimmune disease, myasthenia gravis, in which patients suffer progressive muscle weakness, was found to be caused by antibodies that blocked the actions of the secreted molecules that normally transmit information from the nerves to the muscles. These observations raised the possibility that one type of immune molecule, an antibody, could be used to block the action of another, a cytokine.

To test this hypothesis, Feldmann and Maini obtained an antibody against TNF and initiated a clinical trial in 20 patients with long-standing rheumatoid arthritis that had failed to respond to existing disease-modifying drugs. The results from the onset were astonishing. All 20 patients responded to the treatment and many experienced almost a complete reversal of their swollen joints six weeks after the start of therapy. Drs. Maini and Feldmann went on to organize large, randomized trials to demonstrate the efficacy of TNF antibody in the treatment of chronic rheumatoid arthritis. Not only did these trials demonstrate a dramatic reduction in symptomatology, but over half the patients had improvement in the destructive joint changes they had already undergone, something no other therapy had ever accomplished. Based on the success of these clinical trials, these agents have been approved for therapy in both Europe and the United States. Today, over 300,000 patients have been treated with some form of anti-TNF blocking activity for the treatment of rheumatoid arthritis. This number is currently only limited by the pharmaceutical industry's ability to produce the drugs. More recently, clinical trials have demonstrated the efficacy of TNF blockade in the treatment of other autoimmune diseases including Crohn's disease, an autoimmune disease which destroys the intestines; ankylosing spondylitis, an autoimmune disease that attacks the spine; and psoriasis, an autoimmune disease of the skin. This remarkable story, from inception to clinical approval, took only a decade.

The results of Maini and Feldmann's work have demonstrated that not only is TNF the spark that ignites the inflammatory destruction of the joints in rheumatoid arthritis, but it is also responsible for what keeps the inflammatory fire smoldering between the acute episodes of the disease. Furthermore, the brilliant use of one of the immune system's own defenses to treat an autoimmune disease has demonstrated that Maini and Feldman are modern day medical firefighters: Their use of the antibodies to treat rheumatoid arthritis is truly an example of 'fighting fire with fire'.

Marc Feldmann

Acceptance remarks, 2003 Lasker Awards Ceremony

Ms. Hunt, Mr. Fordyce, Dr. Goldstein, ladies and gentlemen:
It is a great honor to accept the Lasker Award, and a particular pleasure to share it with my colleague and friend of 20 years, Tiny Maini, with whom I have had a most enjoyable collaboration.

As a medical student in Melbourne, I realized we knew very little about disease mechanisms, and was eager to learn more. Gus Nossal offered me the opportunity to do a PhD at the Walter and Eliza Hall Institute in the early days of immune cell culture, with Erwin Diener. My father queried why I no longer wanted to help patients, and I replied glibly that if research worked, instead of helping patients one by one, you could help thousands. Little did I know that this dream would one day come true.

Research was a wonderful experience, in a small Institute peopled by scientific giants Gus Nossal, Jacques Miller, and Don Metcalf (a Lasker Awardee). All members, no matter how junior, were highly valued, and encouraged. Due to the persisting influence of another Lasker Awardee, MacFarlane Burnet, I acquired an interest in the paradox of autoimmunity, and in soluble mediators of immunity and inflammation. At the time these were not characterized, but progress led to their definition as pro-inflammatory proteins, cytokines.

In the early 1980s, I was working in London at the Tumour Immunology Unit, led by Avrion Mitchison. While anti-tumor immunity was evident in animals, it was not in humans, so I decided to explore autoimmune diseases, where there are unwanted immune responses to self, to learn how to induce desirable immune responses to human cancers. But as I developed testable ideas on how autoimmune disease might be generated, I left cancer research to concentrate on autoimmunity. The most accessible human autoimmune disease was rheumatoid arthritis, and the collaboration with Tiny began, which has brought us here today.

Receiving an award as prestigious as this prompts reflection, and gratitude to very many key people. First, to my many scientific collaborators, mentors and friends, and I am glad that some of them are here today. My family has given me enormous pleasure and support. My wife, Tania, has organized a thing called a cultural life and wonderful holidays for us, hiking all over the world. These absences have been invaluable for seeing my research in a much clearer light, and nearly all my new ideas have come while away from the lab. Having fun with my children helped, too.

I have found it an exhilarating adventure, working in science, yet with the opportunity to benefit patients. There is little to match the job satisfaction of seeing a patient treated with your new invention run down the stairs, a week after being barely able to manage them. But that is, if you are lucky, a once in a lifetime event, and persistence in the face of difficulties is more the norm.

My parents gave my brother and me a fine example of how to cope through tough times. After managing by great good fortune to survive the war in Poland, we moved to France, and then emigrated to Australia when I was eight, and arrived knowing no English. There they made a new start, and my father had to become an accountant all over again, in the late 1940s, as his French pre-war degree was not recognized. My parents valued education highly, and were proud that both their sons became doctors. I owe so much to them. They would have been so happy to be here today.

Ravinder N. Maini

Acceptance remarks, 2003 Lasker Awards Ceremony

Dr. Goldstein, Madam President, Chairman, Ladies and Gentlemen.
I feel greatly privileged to be a co-recipient of the Clinical Medical Lasker Award, and especially happy that I am to share this honor with Marc, my friend and close colleague for the past 20 years.

As an undergraduate at Cambridge University, and later at Guy's Hospital in London, I was truly inspired by my teachers and mentors, especially Dr. Charles Baker, a cardiologist, and Professor John Butterfield, the Head of Medicine. Here I was introduced to the scientific basis of medicine, learned the art of practicing bedside medicine, and developed a critical and questioning approach to medical dogma. More importantly, I began to appreciate the importance of clinical measurement. This experience was responsible for a brief foray into measuring pressures and performing angiography by cardiac catheterisation in acquired and congenital diseases of the heart.

I rapidly tired of this mechanical approach and instead became fascinated and excited by the immunological concepts underpinning the emerging field of modern rheumatology. In the late 1960s and early 1970s as a Fellow at The Kennedy Institute of Rheumatology in London, I began to examine the biological activity of soluble factors termed lymphokines or cytokines, elaborated by the interaction of lymphocytes with antigens. I was greatly encouraged at this formative stage to have a paper accepted for publication in Nature, and by an invitation from Barry Bloom to present my work at the First International Congress of Immunology in 1971 in Washington, DC. Next, with Dumonde and based on the ideas and work of Jerry Lawrence at NYU, I embarked on a small placebo-controlled trial of lymphocyte extractable transfer factor in rheumatoid arthritis patients. Needless to say, no significant benefit was observed by this naïve approach using poorly characterised materials.

However, the die was cast and I began work on the immune pathogenesis and biological therapy of rheumatoid arthritis, a disease which I realized wreaks havoc with patients' lives. By the mid-1980s, the field was transformed by molecular and biochemical characterisation of an increasing number of cytokines which we could explore in arthritic tissues. How this path then led to Marc Feldmann's door and our work on the identification of TNF as a key regulator of chronic inflammation has brought us to your attention today.

The benefit that treatment of patients with rheumatoid arthritis have derived from anti-TNF therapy and the expanding indications for treatment of other immune inflammatory diseases has given me immense satisfaction. The single-minded and dogged pursuit of research that I have followed has, however, exacted a price from my family who have consequently lived with my absences. I am particularly indebted to all of them for their tolerance and to my wife, Geraldine, who for the past 20 years has been my muse and inspiration.

Ladies and gentlemen, the Lasker Award, with which you have honored us, will draw attention to the plight of patients with chronic diseases that destroy the quality of life, and will give a signal that scientific discovery can and does alter their future prospects.